G78R
Category 5 — IDR ExclusionConflictingCytoplasmic · predictedEditorialGlycine → Arginine at position 78 in wolframin's N-terminal intrinsically disordered region (IDR). ClinVar carries conflicting classifications. AlphaMissense 0.106 (likely BENIGN by AM, not pathogenic). pLDDT 26 — deep IDR. DynaMut2 ΔΔG -0.48 kcal/mol but NOT trustworthy in this region. A Category 5 IDR variant that requires wet-lab characterization.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | T80 | T80 | Preserved |
| Polar contact | T80 | T80 | Preserved |
| Van der Waals | T80 | — | Lost |
Lost / gained / preserved interatomic contacts at the variant residue, from the DynaMut2 (Arpeggio) interaction analysis of the wild-type and energy-minimized mutant structures.
Computational Predictions
- pLDDT 26.22 below 70
The underlying AlphaFold model has pLDDT below 70 at this position, so the structure the stability calculation was run on is itself uncertain.
Do not rank this value against a variant from a different region on ΔΔG alone.
Clinical Evidence
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Conflicting classifications of pathogenicity for Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); WFS1-related spectrum (unresolved mode) (dominant or recessive). ClinVar records this under a WFS1-spectrum label that spans both disease families — recessive Wolfram syndrome (biallelic) and the dominant WFS1-related disorders. The label does not resolve which applies, and it is not a severity statement.
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- WFS1-related spectrum (unresolved mode)dominant or recessivesubmitted as: WFS1-Related Spectrum Disorders
- Submitters conflict on this classification (1★). Treat the conditions above as submitted, not as documented phenotypes.
- Phenotype scope is interpretation of submitted records. The computed values on this card (AlphaMissense, DynaMut2 ΔΔG, pLDDT) are measurements of the model, not of a patient.
- Presentation cannot be generalised from neighbouring variants: one nucleotide over can present very differently. Structural similarity supports a mechanistic hypothesis, never a phenotype claim.
Review status: 1★ conflicting classifications. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in Admixed American: AF 0.0058% (3 of 51,976 alleles), 3.7x the global figure. The global AF describes the general population, not the at-risk group.
No homozygotes reported in gnomAD v4. For a recessive allele this is expected and is not, on its own, evidence either way.
| Ancestry group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| Admixed American | 0.0058% | 3 / 51,976 | 0 | ~1 in 8660 |
| European (non-Finnish) | 0.0017% | 20 / 1,151,346 | 0 | ~1 in 28780 |
| African / African American · under-sampled | 0.0014% | 1 / 73,454 | 0 | — |
Source: gnomAD r4, retrieved 2026-08-21. Values are allele frequencies. The carrier estimate is derived from the allele frequency (Hardy-Weinberg, ~2·AF) and is an approximation, not a published figure — where a published carrier frequency exists it outranks this column and is cited on the card.
Structural Context
Position 78 sits in wolframin's N-terminal intrinsically disordered region (IDR), spanning residues 1–86. The pLDDT score of 26 indicates that AlphaFold's predicted geometry at this position is essentially unreliable — the structure shown in the model does not represent a single dominant conformation but rather an arbitrary picked sample from an ensemble.
The AlphaFold-derived neighbor analysis shows only PRO79 (2.5 Å) and THR77 (2.5 Å) — the immediate sequence neighbors and nothing else within 5 Å. This is itself a structural signature of IDR: in folded domains, every residue has multiple cross-chain neighbors at structural contact distance. In IDRs, only sequence neighbors appear because the chain has no consistent tertiary structure.
The DynaMut2 |ΔΔG| of 0.48 kcal/mol is therefore not trustworthy as a quantitative claim about the variant's structural impact. DynaMut2 assumes a meaningful input fold; IDR positions violate that assumption.
What is more revealing is the AlphaMissense score of 0.106 — well below the 0.564 likely-pathogenic threshold. AlphaMissense considers this variant likely benign. And yet ClinVar carries conflicting classifications including documented Wolfram-related conditions. The disconnect suggests either: (a) the variant is genuinely benign and clinical reports represent false-positive pathogenic calls or population-stratification artifacts; (b) the variant is pathogenic by a mechanism (e.g., IDR-mediated phase separation, partner binding through disordered region) that AlphaMissense's training does not capture; or (c) the variant's pathogenicity depends on context (e.g., compound heterozygosity with another WFS1 variant) that single-variant analysis cannot resolve.
None of these can be settled from the structural data alone.
Druggability Assessment
The Atlas explicitly routes Category 5 variants away from computational drug discovery and toward wet-lab characterization. Recommended next steps: (1) confirm clinical penetrance with additional case data; (2) characterize the IDR's role in wolframin partner interactions experimentally; (3) test the variant in cell-based functional assays before drawing therapeutic conclusions.
Until experimental data clarifies the mechanism, this variant should NOT drive therapeutic strategy.
Why this matters
Feed this card to Wolfram Intelligence
Download the G78R PDF below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals — guanidinium mimetics, sigma-1 agonist docking, NAC thiol-capping. NAC is already on the bench-testing list.